The invention relates to an improved process for phosphorylation of organic hydroxyl groups and the compounds produced using this process.
In this specification, where a document, act or item of knowledge is referred to or discussed, this reference or discussion is not to be taken as an admission that the document, act or item of knowledge or any combination thereof was at the priority date:
(a) part of common general knowledge; or
(b) known to be relevant to an attempt to solve any problem with which this specification is concerned.
Whilst the following discussion highlights the invention with respect to dietary supplements, it is believed that the same principles apply to other compounds containing organic hydroxyl groups such as pharmaceutical compounds with hydroxyl groups.
The use of dietary supplements is well known, for example hormones, phytosterols or chromans. One of the problems encountered with such supplements for human ingestion is that many of the supplements are relatively water insoluble but the human digestive tract is a substantially aqueous system. Previous attempts to overcome this problem include using emulsifiers to enable an oil-based solution of the supplement to combine with an aqueous system and thus maintain the supplement""s bioavailability. Consequently, it would be useful to be able to convert these dietary supplements to water soluble compounds without disturbing their inherent structure. Phosphate salts with either potassium or sodium are already found in biological tissue. Therefore phosphate salts should be tolerated by the body.
There is a diverse art for the production of organic phosphates, however none of these methods are considered to be suitable for production of complex phosphate compounds because they are either unsuitable for use on a commercial scale or there are side reactions which produce undesired by-products.
Ordinarily, phosphorylation reagents and methods are chosen to avoid significant degradation of the compound being phosphorylated. Where gentle conditions are required, then reagents such as 2:2:2-trichloroethyl dichlorophosphate, di-imidazolide chlorophosphate and di-analide chlorophosphate have been employed but have limited yields which are inadequate for commercial processes. When more severe conditions are feasible, then phosphorous oxychloride has been used, but the reaction produces a variety of by-products together with hydrogen chloride. There are other problems associated with the fact that phosphorous oxychloride is difficult to manage which make this reagent unsuitable for use on a commercial scale.
Although P4O10 [which is often incorrectly called phosphorous pentoxide] has been used for phosphorylation of ethanol and other short chain primary alcohols, it has not been used for higher alcohols and complex molecules because the temperatures used are too high and there is considerable degradation. Another reason why P4O10 is not used for higher alcohols and complex molecules is that at the higher temperatures used in known P4O10 processes, there is formation of a significant amount of by-products. Even with ethanol, there is a significant amount of diethylphosphate as well as monoalkylphosphate which is produced and these substances must be removed. Commercial processes use P4O10 with ethanol but there is a complicated clean-up procedure because the reaction occurs at a high temperature.
Further, with secondary or tertiary alcohols P4O10 causes dehydration and formation of a double bond. This dehydration is further promoted by the high temperatures at which this reaction takes place. In fact, this is a standard reagent and method for forming a double bond. This reaction has thus been considered to be unsuitable for production of complex phosphate compounds.
It is the need for lower temperatures which has led to the use of POCl3 because, in the presence of a base, a lower temperature can be used and degradation is avoided. POCl3 is the preferred method for phosphorylating complex molecules.
There is, therefore, a need for a reliable process for phosphorylating complex compounds so that these compounds can be used in aqueous environments.
It has surprisingly been found that P4O10 can be used to phosphorylate primary fatty alcohols, secondary alcohols (including cyclohexanols) and aromatic alcohols (including phenols and chromanols). In this description and in the claims, the term xe2x80x9ccomplex alcoholsxe2x80x9d refers to primary fatty alcohols, secondary alcohols and aromatic alcohols. The complex alcohols include hormones, phytosterols, tocopherols (chromans), vitamin K1 and other oil-soluble vitamins and dietary supplements as well as pharmaceutical compounds such as Amoxycillin.
In this description, the word xe2x80x9cintimatexe2x80x9d is used to signify its technical meaning as known to persons skilled in the art. That is, to signify that two substances are in very close physical contact dispersed as particles which are as small as possible so that a reaction is initiated. There must be as large a surface area as possible for the reaction to initiate and this is also advantageous for further reaction.
Accordingly, there is provided a process for phosphorylating complex alcohols comprising the following steps:
(a) forming an intimate mixture of one or more complex alcohols and P4O10 at a temperature below 80xc2x0 C. in the absence of additional solvents; and
(b) allowing the intimate mixture to continue to react for a period of time at a temperature below 80xc2x0 C. until the formation of the dihydrogen form of the phosphorylated complex alcohol is substantially completed.
It is understood that in steps (a) and (b), the temperature is sufficient to ensure there is minimum degradation of the complex alcohols but the reaction will still proceed to a satisfactory extent.
The complex alcohols must be in a liquid phase at the desired temperature of reaction. Persons skilled in the art will be aware that some complex alcohols are commercially supplied in a stabilizing medium. Such complex alcohols may be used in this process without removing the stabilizing medium.
Preferably, where minimum degradation is desired, the temperature at which the reaction is performed is in the range from 0 to 50xc2x0 C. More preferably, the temperature is in the range from 0 to 40xc2x0 C.
Preferably where the period of time in step (b) is minimized, the temperature at which the reaction is performed is about 70xc2x0 C.
The ratio of P4O10 to complex alcohols will depend on the temperature at which the reaction occurs. At the higher temperatures, the ratio of phosphorus to complex alcohols is substantially equimolar. That is, at the higher temperatures there is more efficient consumption of the phosphate groups. At the lower temperatures, the ratio of P4O10 to complex alcohols is substantially equimolar.
The period of time in step (b) is dependent on the temperature at the ratio of reagents. Where there is equimolar phosphorus, preferably the period of time does not exceed about 30 minutes. Where there is equimolar P4O10, preferably the period of time does not exceed about 10 minutes.
The choice of temperature at which the reaction occurs is dependent on the expense of the complex alcohols. For example, Amoxycillin is expensive therefore it is preferable to minimize the degradation of Amoxycillin.
Where lower temperatures are used and there are unreacted reagents, the unreacted reagents can be recycled. For example, if the temperature is between 0 to 40xc2x0 C., the process would further comprise a step where the unreacted reagents were mixed with more P4O10 and complex alcohol and steps (a) and (b) repeated.
The phosphorylated complex alcohols may be recovered as either the acid or as a salt (usually potassium or sodium) using methods known to those skilled in the art. For example, the reaction mixture from step (b) may be neutralized with potassium or sodium hydroxide then the water evaporated to recover the salt.
The pressure is typically at atmospheric because there is no advantage using higher pressures at these temperatures.
The intimate mixture is formed using methods known to those skilled in the art. Vigorous stirring is typically necessary to achieve an intimate mixture. In a laboratory, a mortar and pestle can be used. In an industrial plant, a high shear mixer would be used.
According to a preferred embodiment, formation of the intimate mixture in step (a) is performed in the presence of an aliphatic carboxylic acid excluding formic and acetic acid. In this description and in the claims, the term xe2x80x9caliphatic acidxe2x80x9d refers to any aliphatic carboxylic acid except for formic acid and acetic acid. Preferably, the aliphatic acid is a free fatty acid. Examples include oleic acid and stearic acid. The aliphatic acid acts as a catalyst for the reaction and reduces the side reactions.
According to another form of the invention, there is provided a phosphate derivative of a complex alcohol which was produced by the above process.